Systemic injection of adult neural stem cells (aNSCs) into mice with experimental autoimmune encephalomyelitis (EAE) can provide a source of new oligodendrocytes that can remyelinate demyelinated or dysmyelinated axons. However, systemically-injected aNSCs often fail to differentiate and remain undifferentiated in peri-vascular domains of demyelinated lesions where they promote apoptosis of blood-born CNS-infiltrating encephalitogenic T cells. These data suggest that the microenvironments of demyelinated lesions dictate whether aNSCs differentiate into cells with the capacity to promote remyelination or remain undifferentiated and promote neuroprotection by inducing T cell apoptosis. We recently discovered that a high molecular weight form of hyaluronan (HA), a glycosaminoglycan, accumulates in demyelinated lesions and reversibly inhibits oligodendrocyte progenitor cell maturation. The major receptor for HA, the CD44 transmembrane glycoprotein, is expressed by activated T cells and by NSCs, and has been implicated in T cell extravasation across the blood-brain barrier in mice with EAE as well as in regulating how cells respond to HA. Our preliminary data suggest that HA and CD44 may regulate functions relevant to how aNSCs behave in demyelinated lesions, including NSC differentiation and the production of pro-inflammatory cytokines. We propose that CD44 and HA are critical mediators of aNSC recruitment to demyelinated lesions and that HA, at least, can regulate whether NSCs differentiate into myelinating cells or fail to differentiate and promote T cell apoptosis at perivascular domains where HA accumulates. In the studies outlined in this proposal, we aim to test the hypotheses: (1) That high molecular weight HA inhibits aNSC differentiation; (2) That NSC homing to EAE lesions depends on interactions between CD44 and HA; and (3) That HA regulates the immunomodulatory activities of NSC PROJECT RELEVANCE: These studies are aimed at determining how altering the extracellular matrix within demyelinating lesions influence the ability of adult neural stem cells to differentiate into cells that can remyelinate affected axons. Our studies should provide fundamental insights into how to optimally utilize neural stem cells to treat multiple sclerosis and related diseases. [unreadable] [unreadable] [unreadable]